Background: Sequential therapy with different novel androgen receptor signaling inhibitors (ARSIs) is a possible treatment option for patients who have increased prostate-specific antigen (PSA) levels. The aim of the present study was to investigate cross-resistance among ARSIs and its predictors in non-metastatic castration-resistant prostate cancer (nmCRPC).
Methods: In this multicenter retrospective study, we evaluated 75 patients with nmCRPC who had progressed after treatment with one ARSI and were subsequently treated with a second ARSI. The primary endpoint was cross-resistance among ARSIs, which was identified by comparing PSA responses to treatment with first and second ARSIs. The secondary endpoints were changes in PSA doubling time (PSADT) from diagnosis of nmCRPC to initiation of treatment with a second ARSI and predictors of PSA non-responsiveness to treatment with that second ARSI.
Results: The rates of any PSA response, PSA decline ≥ 50%, and PSA decline ≥ 90% to treatment with a second ARSI were significantly lower than those to the first ARSI administered (45% vs. 88%, P < 0.001; 9.3% vs. 71%, P < 0.001; 2.7% vs. 33%, P < 0.001; respectively). The PSADT shortened to some degree in 31 patients (41%). According to multivariable analysis, only PSADT before initiation of treatment with a second ARSI was significantly associated with no PSA response to treatment with that second ARSI.
Conclusions: We identified significant cross-resistance among ARSIs in patients with nmCRPC. The PSADT before initiation of treatment with a second ARSI may be useful for predicting the efficacy of treatment with a second ARSI.
Keywords: Cross-resistance; Non-metastatic castration-resistant prostate cancer; Novel androgen receptor signaling inhibitor; Predictor; Prostate-specific antigen response; Sequential therapy.
© 2025. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.